Description of Research Expertise

The major focus of the laboratory is the process by which the binding of hormones to cell-surface receptors is translated into the regulation of target enzymes and ion channels. The Manning laboratory is specifically interested in pathways of transduction defined by heterotrimeric GTP-binding regulatory proteins (G proteins). Current studies include mapping linkages among receptors and G proteins in intact cells, defining post-translational modifications of G protein subunits that influence targeting and protein-protein interactions, and exploring the roles of novel G proteins. Considerable effort in the laboratory is devoted toward understanding the relevance of G proteins to the actions of the Hedgehog morphogens. We are currently pursuing noncanonical forms of signaling achieved by Hedgehogs using the Gi family of G proteins. We are also interested in the activation of the one or more forms of Gli transcription factors by ligands apart from Hedgehogs, and specifically through receptors that couple to the G12/13 family. Pursuit of these interests have required the development of methods to evaluate the communication of receptors with G proteins, with an emphasis placed on determinants of efficacy. The idea that ligands working through a single receptor can generate different signals (functional selectivity), or that these signals can be generated by a single ligand as function of ligand concentration, represents a common theme of the work.

Description of Itmat Expertise

I have a primary interest in 7-transmembrane receptors and the heterotrimeric G proteins with which they communicate. My research is currently focused on signaling by the 7-TM receptor Smoothened, which is employed by Sonic hedgehog and whose mutation underlies a variety of developmental defects and cancers. My interests also include functional selectivity and allosterism as it applies to ligands for receptors operating through the G12/13 family of G proteins.